Epidemiologic data suggest that there has been a significant rise in calories from saturated fat and fructose rich foods in the western world (Bray G A et al., Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity. Am J Clin Nutr 2004; 79:537-543). This increase in consumption has been paralleled by an increasing prevalence of obesity and its associated hepatic comorbidity, nonalcoholic fatty liver disease (NAFLD) (Cave M et al., Nonalcoholic fatty liver disease: predisposing factors and the role of nutrition. J Nutr Biochem 2007; 18:184-195). Studies of NAFLD indicate that the presence of fibrosis within the more severe phenotype, nonalcoholic steatohepatitis (NASH), is an important predictor of adverse long-term health outcomes.
Understanding the progression of fibrosis in NASH has been hampered by the lack of a comprehensive and physiologic small animal model of NASH with fibrosis. To date, small animal models of NASH with fibrosis involve either genetic manipulation (Watanabe S et al., Hepatocyte-specific Pten-deficient mice as a novel model for nonalcoholic steatohepatitis and hepatocellular carcinoma. Hepatol Res 2005; 33:161-166; Saxena N K et al., Leptin in hepatic fibrosis: evidence for increased collagen production in stellate cells and lean littermates of ob/ob mice. Hepatology 2002; 35: 762-771; Oben J A, et al., Norepinephrine induces hepatic fibrogenesis in leptin deficient ob/ob mice. Biochem Biophys Res Commun 2003; 308:284-292), forced overfeeding (Baumgardner J N et al., A new model for nonalcoholic steatohepatitis in the rat utilizing total enteral nutrition to overfeed a high-polyunsaturated fat diet. Am J Physiol Gastrointest Liver Physiol 2008; 294:G27-38), or contrived diets deficient in methionine and choline (MCD) (Leclercq I A et al., CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis. J Clin Invest 2000; 105:1067-1075; George J et al., Lipid peroxidation, stellate cell activation and hepatic fibrogenesis in a rat model of chronic steatohepatitis. J Hepatol 2003; 39:756-764; Sahai A et al., Upregulation of osteopontin expression is involved in the development of nonalcoholic steatohepatitis in a dietary murine model. Am J Physiol Gastrointest Liver Physiol 2004; 287:G264-273; Rinella M E et al., Mechanisms of hepatic steatosis in mice fed a lipogenic methionine choline-deficient diet. J Lipid Res 2008; 49:1068-1076). These models fail to map to key aspects of what occurs in human beings. For example, few humans experience diets that are deficient in methionine and choline. Moreover, rodents exposed to MCD diets are not obese. Rather, they lose weight and actually become more insulin sensitive (Rinella M E et al., Mechanisms of hepatic steatosis in mice fed a lipogenic methionine choline-deficient diet. J Lipid Res 2008; 49:1068-1076).